title: A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy.
abstract: BACKGROUND
  Oncolytic adenoviral virotherapy (OV) is a highly promising approach for the treatment of glioblastoma multiforme (GBM). In practice, however, the approach is limited by poor viral distribution and spread throughout the tumor mass.
  
  
  METHODS
  To enhance viral delivery, replication, and spread, we used a US Food and Drug Administration-approved neural stem cell line (NSC), HB1.F3.CD, which is currently employed in human clinical trials. HB1.F3.CD cells were loaded with an oncolytic adenovirus, CRAd-Survivin-pk7, and mice bearing various human-derived GBMs were assessed with regard to NSC migration, viral replication, and therapeutic efficacy. Survival curves were evaluated with Kaplan-Meier methods. All statistical tests were two-sided.
  
  
  RESULTS
  Antiglioma activity of OV-loaded HB1.F3.CD cells was effective against clinically relevant human-derived glioma models as well as a glioma stem cell-enriched xenograft model. Median survival was prolonged by 34% to 50% compared with mice treated with OV alone (GBM43FL model median survival = 19.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.26, 95% confidence interval [CI] = 1.21 to 12.23, P = .02; GBM12 model median survival = 43.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.53, 95% CI = 1.21 to 10.38, P = .02). OV-loaded HB1.F3.CD cells were shown to effectively migrate to the contralateral hemisphere and hand off the therapeutic payload of OV to targeted glioma cells. In vivo distribution and migratory kinetics of the OV-loaded HB1.F3.CD cells were successfully monitored in real time by magnetic resonance imaging. OV-loaded NSCs retained their differentiation fate and were nontumorigenic in vivo.
  
  
  CONCLUSIONS
  HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7 overcome major limitations of OV in vivo and warrant translation in a phase I human clinical trial for patients with GBM.
authors.affiliation: The Brain Tumor Center, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.forename: Bart
authors.initials: B
authors.lastname: Thaci
authors.forename: Alex L
authors.initials: AL
authors.lastname: Tobias
authors.forename: Brenda
authors.initials: B
authors.lastname: Auffinger
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Cheng
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.forename: Catherine
authors.initials: C
authors.lastname: Yunis
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.forename: Nikita G
authors.initials: NG
authors.lastname: Alexiades
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Fan
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D058953:Neural Stem Cells / Q000637:transplantation*; D050130:Oncolytic Virotherapy / Q000379:methods*; D033581:Stem Cell Transplantation / Q000379:methods*; D023041:Xenograft Model Antitumor Assays